article · Journal of Enzyme Inhibition and Medicinal Chemistry
Two series of hydroxamic acid hybrid compounds were designed and synthesised to act as histone deacetylase inhibitors for cancer therapy. When tested against prostate cancer and osteosarcoma cell lines, one candidate, designated compound 5d, demonstrated the strongest antiproliferative activity against the DU-145 and PC-3 prostate cancer lines. This lead molecule actively inhibited histone deacetylase enzymes 2, 4, 6, and 8 at low micromolar concentrations. Biological evaluations showed that the compound triggered apoptotic cell death across the tested cell lines, causing cell cycle arrest in the S phase for prostate cancer cells and in the G0/G1 phase for osteosarcoma cells. Computational docking and molecular dynamic simulations confirmed stable binding between the compound and its target enzymes. These findings suggest that the compound holds promise for managing prostate cancer, particularly cases involving bone metastasis.
Prostate cancer often spreads to bone, creating advanced disease that is difficult to manage with current therapies. By designing a molecule that simultaneously inhibits multiple histone deacetylase enzymes, this research offers a potential pathway towards dual-action treatments capable of curbing both primary prostate tumours and associated secondary bone growths.
This work is at an early discovery stage, relying on laboratory cell cultures and computational simulations. The findings could interest oncology drug developers and pharmaceutical companies seeking lead compounds for advanced prostate cancer therapies, particularly where bone metastasis is present. Translating this candidate into a viable therapeutic will require further optimisation, extensive pre-clinical animal studies, and pharmacokinetics testing before any clinical trials can occur.
AI-generated from the published abstract. Always read the original work before citing.
Two novel series of hydroxamic acid hybrids were designed and synthesised as anticancer agents via histone deacetylase isozymes (HDACs) inhibitors. Antiproliferative effects of novel compounds were evaluated against DU-145 and PC-3 (prostate cancer) and MG-63 (osteosarcoma) cell lines. Compound 5d emerged as the most potent against DU-145 and PC-3 (prostate cancer) with IC50 values of 0.93 and 1.05 µM, exhibiting inhibiting HDAC 2, 4, 6, and 8 with IC50 values of 0.86, 0.17, 1.17, and 0.15 µM respectively. As a result, it was selected for mechanistic investigations. Apoptotic cell death modality was predominantly detected in the three cell lines, accompanied by cell cycle arrest in the S phase in prostate cancer cell lines, whereas it caused cell cycle arrest in MG-63 osteosarcoma cells in the G0/G1 phase. Docking studies confirmed its high affinity for HDACs, and an atomistic standard 100 ns dynamic simulation supported the stability of these interactions. In conclusion, all these findings suggested the potential use of this compound for treating prostate cancer with bone metastasis.
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DOI: 10.1080/14756366.2026.2711875
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